Alzheimer's Disease Imaging Options Examined at MEDICA 2011

September 1, 2011 – As with all chronic illnesses, it is everyone's dream to be able to diagnose Alzheimer's disease in the early stages. Naturally, the aim is to prevent the late stage, i.e. dementia, through early therapy. Scientists around the world are making ever more progress in early diagnosis – for instance, in the field of imaging technologies. What is already diagnostically possible today will be showcased at MEDICA 2011, the world's largest medical trade fair and congress to be held from Nov. 16–19, 2011 in Düsseldorf, Germany, with more than 4,500 exhibitors from 60 countries.

Just months ago, experts in the United States published new recommendations for the diagnosis of Alzheimer's disease, which differentiate between three overlapping stages:

• The preclinical stage (Stage I)

• The stage of mild cognitive impairment (MCI) (Stage II)

• The dementia stage.

Today, the dementia stage can be diagnosed with considerable certainty through a combination of anamnesis, psychometric tests, imaging procedures and chemical parameters (biomarkers in blood serum). However, up to now, the therapy options for this stage have not been very effective. In order to possibly achieve more through early drug therapy, Alzheimer's researchers around the world are increasingly focusing on methods that diagnose the neurodegenerative disease before the onset of dementia. They are concentrating their efforts on the MCI stage (Stage II). Annually, ten to twenty percent of MCI patients develop dementia. The challenge is to recognize those patients with certainty. In addition to anamnestic findings, psychometric tests and blood serum analyses, there are essentially two imaging procedures that are relevant for early diagnostics: positron emission tomography (PET) and magnetic resonance imaging (MRI) and its various procedures. The leading manufacturers of these procedures – for instance, GE Healthcare, Siemens Healthcare and Philips Healthcare – are exhibitors at MEDICA 2011.

Direct Amyloid Imaging: PET Makes it Possible

Currently, PET is getting a lot of interest, such as with radioactive tracers such as fluorodesoxyglycose (FDG) to detect cerebral glucose metabolism disorders, but primarily with radioactively marked active agents for direct amyloid imaging. Examples of such tracers include florbetaben (Bayer Schering), florbetapir (Lilly), flutemetamol (GE Healthcare) and Pittsburgh Compound B (PiB – license holder GE Healthcare). These substances bind to beta amyloid in the brain, which can be measured with a PET camera. This provides data that, together with MRI data, allow a precise localization of the beta amyloid. This direct amyloid display is a combined diagnostic method using PET and MRI. Developed by Siemens Healthcare, the Biograph mMR is a total body system with simultaneous MRI and PET which, within the framework of clinical trials, has been installed at several university hospitals in Germany and the United States for the past year. The system received U.S. Food and Drug Administration (FDA) approval in June 2011 and, thanks to its CE certification, is now also in regular use in hospitals in the European Union.

A so-called hybrid system comprising a total-body PET/MRI scanner, equipped with Philips technology, was also installed at the University Hospital of Geneva last year. However, PET is not suitable for diagnosing Alzheimer's in day-to-day medical practice. Problems using PET to diagnose amyloids include low availability and the relatively high degree of complexity as well as the cost (about 1,250 to 1,500 Euros per examination). In addition, the accumulation of beta-amyloids is a prerequisite for developing Alzheimer's dementia but, based on current knowledge, this is not enough. The clinical significance of the amyloids detected by PET is not yet entirely clear, explained the neurologist and professor Hansjörg Bäzner, chief physician at Stuttgart's Bürgerhospital.

Important additional information through functional MRI procedures

Conventional, non-functional MRI has long been a routine procedure in the diagnosis of dementia, above all for differential diagnosis of various forms of dementia and cerebral diseases that may be accompanied by cognitive disorders like vascular damage, brain tumors and inflammations. Functional and special MRI procedures for the diagnosis of early-stage Alzheimer's are promising but, similar to PET, are still mostly limited to research. "Initial studies indicate that it is voxel-based morphometry, MR spectroscopy and diffusion tensor imaging that may be the primary sources of important additional information," explained Thomas Hauser, M.D., of the German Cancer Research Center.

With voxel-based morphometry (VBM), the brain volume is measured to determine the amount of gray or white matter or of brain fluid / bone (voxel is a coined word that combines the words "volume" and "element"; three-dimensional equivalent of a pixel). All the MRI images of the examined brains are scaled to the same size so that a comparison can be made between a number of people. According to Hauser, VBM allows (independent of the respective investigator) a quick, almost completely automated quantification of changes in the brain that are characteristic of Alzheimer's, like atrophy of the hippocampus (loss of matter in certain areas of the brain).

In addition, there are positive results from early diagnosis with various functional MRI procedures, like magnetic resonance spectroscopy (MRS). This non-invasive procedure can measure water in the living brain as well as metabolic products – currently more than 16 metabolites. The lower detection threshold is 1 millimole; this means that substances with a concentration 100,000 times lower than water can be detected. The best-researched and most important metabolites in the early diagnosis of dementia are N-acetyl-aspartate (NAA), choline (Cho), creatine (Cr) and myoinositole (mI). NAA is a marker for intact neurons, Cho is considered a marker for cell proliferation, Cr is an indicator for intact energy metabolism of cells, and ml contributes to intracellular signal processing. Another non-invasive MRI procedure is diffusion-weighted magnetic resonance imaging (DW-MRI), which measures and displays in 3-D the diffusion of water molecules in tissue. It is primarily used to examine the brain, as with several diseases of the central nervous system (CNS) the diffusion behavior undergoes characteristic changes. Diffusion tensor imaging (DTI) is a variant of DW-MRI. According to Hauser, in contrast to volumetric measurements, these complex procedures reflect microscopic tissue changes.

Everyday Risk Score Calculator Developed for Predicting Dementia

As fascinating as imaging procedures are, they represent only a small piece in the jigsaw puzzle of Alzheimer's diagnosis. Other relevant pieces in the puzzle are still anamnesis, clinical findings as well as neuropsychological tests and serum parameters (beta-amyloid, total tau, phospho-tau and amyloid precursor proteins). As well, a patient's own admission that he/she is becoming forgetful should be a warning flag.

Because, as psychiatrist and professor Frank Jessen of Bonn has discovered, an above average number of patients who are merely concerned about their forgetfulness frequently develop dementia. Together with colleagues, Jessen developed a risk score calculator with which quite a precise prognosis of the risk of developing Alzheimer's is allegedly possible. Based on this risk score calculator, which requires anamnestic data as well as cognitive tests, family physicians are able to advise patients and their families as well as start initial preventive and therapeutic steps. According to Bäzner, although there are no pharmacological or non-pharmacological treatments that without any doubt, in the sense of evidence-based medicine, are proven to protect MCI patients from dementia, there are indications that good blood pressure and blood sugar regulation, losing excess weight, and endurance sports can help. In any case, "therapeutic nihilism" is, with certainty, the wrong approach in a concrete treatment situation.

Dementias are the focus at the MEDICA Congress, including at the seminars "Demographic change and dementia" (November 17), no. 203, headed by professor Ingo Füsgen, M.D., and "The elderly patient and neurological diseases" (November 18), no. 313, headed by professor Stefan Isenmann, M.D., (both held at the Congress Center Düsseldorf, CCD South).

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This figure shows two different brains that are aligned to a common template space for comparison. The yellow in the anterolateral entorhinal cortex of the young brain indicates significant activity, something that is absent in the older brain. CREDIT: Zachariah Reagh

Representative PET/CT images of 18F-FDS and 18F-FDG in inflamed mice. Mice were inoculated with dead K. pneumoniae (10^8 CFU/mL). Imaging was performed for days 1, 2, 3 and 4 using 18F-FDG and 18F-FDS. CT images showed clear inflammation on day 2 and day 3 with corresponding high 18F-FDG uptake on PET. No significant uptake of 18F-FDS was detected for any of those 4 days. Credit: J Li et al., University of Louisville School of Medicine, Louisville, Ky.